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The Slow and Long-Lasting Blockade of Dopamine Transporters in Human Brain Induced by the New Antidepressant Drug Radafaxine Predict Poor Reinforcing Effects Nora D

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The Slow and Long-Lasting Blockade of Dopamine Transporters in Human Brain Induced by the New Antidepressant Drug Radafaxine Predict Poor Reinforcing Effects Nora D The Slow and Long-Lasting Blockade of Dopamine Transporters in Human Brain Induced by the New Antidepressant Drug Radafaxine Predict Poor Reinforcing Effects Nora D. Volkow, Gene-Jack Wang, Joanna S. Fowler, Susan Learned-Coughlin, Julia Yang, Jean Logan, David Schlyer, John S. Gatley, Christopher Wong, Wei Zhu, Naomi Pappas, Michael Schueller, Millard Jayne, Pauline Carter, Donald Warner, Yu-Shin Ding, Colleen Shea, and Youwen Xu Background: (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce Ͼ50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain. Methods: PET and [ 11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel. Results: DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed. Conclusions: The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics. Key Words: PET, kinetics, abuse, reinforcement, striatum prevent people from taking medication regularly. Radafaxine is the (ϩ) isomer of hydroxybupropion (Sanchez and Hyttel 1999). epression is one of the most prevalent psychiatric disor- Hydroxybupropion is chiral, and the ability to block the DAT and NERT resides in the (ϩ) isomer, radafaxine (Sanchez and Hyttel ders of adulthood (Kessler et al 1994). The lifetime ϩ prevalence for major depression in the United States in 1999). The ( ) isomer of hydroxybupropion also seems to D underlie the efficacy of hydroxybupropion in a mouse model of persons 15–54 years of age has been estimated to be 17.1% (Blazer et al 1994). Although there are a wide variety of depression (forced swimming) (Damaj et al 2004). In addition, ␣ ␤ antidepressant medications, there is still need for newer medica- this isomer is also an antagonist of the 4 2 nicotine receptor tions. There are still a significant number of depressed patients and has been shown to interfere with the acute effects of nicotine who do not respond or have inadequate responses; the overall in mice (Damaj et al 2004). mean response rate for antidepressants was recently estimated to A concern regarding drugs that block DAT is that they might be 62% (Lam et al 2002). It would also be desirable to develop be reinforcing (Ritz et al 1987). Indeed, human imaging studies new antidepressant drugs with a better safety margin and fewer have shown a linear relationship between the degree of DAT side effects than those currently available. blockade by drugs such as cocaine and methylphenidate (MP) In the study reported here, we evaluated a new antidepres- and their reinforcing effects when they are injected intravenously sant drug (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpho- (IV), as assessed by self-reports of drug effects such as “high” and linol hydrochloride (radafaxine; GlaxoSmithKline, Research Tri- “rush” (Volkow et al 1997, 1999b). Using positron emission angle Park, North Carolina). The efficacy of radafaxine in tomography (PET), we have assessed the properties of DAT- depression is attributed to its activity at both the dopamine blocking drugs that are associated with their reinforcing effects. transporters (DAT) and the norepinephrine transporters (NERT) We have shown that for these drugs to be reinforcing, they have (Sanchez and Hyttel 1999). It is thought that radafaxine might to block more than 50% of the DAT within a relatively short Ͻ have advantages over other antidepressants in terms of reduced period ( 15 min from administration) and clear the brain rapidly side effects, such as diarrhea and nausea, which very often to enable fast repeated administration (Volkow et al 1995a, 1997, 1998). In this study, we used PET to evaluate the effects of radafax- From the Brookhaven National Laboratory (NDV, G-JW, JSF, JY, JL, DS, JSG, CW, NP, MS, MJ, PC, DW, Y-SD, CS, YX), Upton; Departments of Psychiatry ine at the DAT in the human brain (potency and pharmacoki- (NDV) and Mathematics (WZ), State University of New York at Stony netics) as a means to predict its reinforcing effects and hence its Brook, Stony Brook, New York; and GlaxoSmithKline (SL-C), Research abuse liability. Dopamine transporter blockade was measured 11 Triangle Park, North Carolina. with the DAT radioligand [ C]cocaine in eight healthy control Address reprint requests to Nora D. Volkow, M.D., Brookhaven National subjects. To assess the pharmacokinetics of DAT blockade, we Laboratory, Medical Department, Upton, New York 11973; E-mail: measured DAT blockade at different times after radafaxine [email protected]. administration (1, 4, 8, and 24 hours) in each individual, in Received July 27, 2004; revised November 29, 2004; accepted December 4, addition to a baseline [11C]cocaine scan before drug administra- 2004. tion. To assess the level of DAT occupancy by radafaxine, we 0006-3223/05/$30.00 BIOL PSYCHIATRY 2005;57:640–646 doi:10.1016/j.biopsych.2004.12.007 © 2005 Society of Biological Psychiatry N.D. Volkow et al BIOL PSYCHIATRY 2005;57:640–646 641 selected a dose of 40 mg, which is the targeted dose for the late distribution volume ratios in caudate, putamen, and ventral treatment of depression. The behavioral and cardiovascular striatum, with a graphic analysis technique for reversible systems responses to radafaxine were monitored during the PET studies. (Logan et al 1990), modified to avoid arterial sampling (Logan et al 1996). The distribution volume ratio, which is the ratio of the Methods and Materials distribution volume (DV) in striatum to that in cerebellum (DVSTR/DVCB) and which corresponds to the binding potential Subjects Bmax/Kd ϩ1, was used as an estimate of DAT availability (Logan Ϯ Ϯ Eight healthy male subjects, 31 6 years of age (mean SD), et al 1994, 1996). Dopamine transporter occupancies were were studied. Written informed consent was obtained from all Ϫ calculated as [(Bmax/Kdbaseline Bmax/Kdradafaxine)/Bmax/ subjects after a complete description of the study and following ϫ Kdbaseline] 100. the guidelines set by the institutional review board at To determine whether radafaxine significantly induced DAT Brookhaven National Laboratory (Upton, New York). blockade, we performed one-way repeated-measures analysis of variance (ANOVA), comparing the Bmax/Kd at different times. PET Scan ϩ Upon rejection of the ANOVA hypothesis of equal DAT blockade The PET studies were carried out with an HR tomograph across time, we used the Dunnett method for comparison with a (resolution 4.5 ϫ 4.5 ϫ 4.5 mm full width half-maximum, 63 11 control to compare the Bmax/Kd obtained at different times after slices), with [ C]cocaine used as a DAT ligand (Fowler et al radafaxine administration with the baseline, controlling the ex- 1989). Methods for positioning of subjects, catheterizations, perimentwise error rate to be .05 (two-sided). To assess whether transmission scans, and blood sampling and analysis have been the levels of DAT occupancy differed for the different time points published (Fowler et al 1989). Briefly, emission scans were after radafaxine administration, we performed repeated-mea- started immediately after injection of 4–8 mCi of [11C]cocaine Ͼ ␮ sures ANOVA, and post hoc pairwise comparisons were then (specific activity .2 Ci/ mol at time of injection). A series of 20 done with the Tukey method, controlling the experimentwise emission scans were obtained from time of injection to 54 min. 11 error rate at .05 (two-sided) to assess at which time points the Subjects were scanned five times with [ C]cocaine over a DAT occupancies differed. Stepwise regression and the least 2-day period; the first scan was done with no intervention and squares method were used to fit the temporal curves of plasma was used as a baseline, and the other four scans were performed drug concentration and DAT occupancy and to find the paramet- 1 hour, 4 hours, 8 hours, and 24 hours after a single oral ric relationship between plasma radafaxine concentration and administration of 40 mg of radafaxine. Venous blood was drawn DAT occupancy in striatum. Spearman’s rank correlation analysis for quantification of plasma concentrations of radafaxine before was used to further examine the relationship between DAT and at .5, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 8.5, 9, 12, 24, 24.5, and occupancy and the concentration of radafaxine in plasma. For 25 hours after administration of radafaxine. Human plasma the comparison of cardiovascular measures, we averaged the samples were assayed for radafaxine with a method based on measures taken just before and during the first 30 min of each protein precipitation with acetonitrile, followed by liquid chro- scan. For the comparisons of the descriptor of drug effects, we matography/mass spectometry/mass spectometry (liquid chro- also averaged the measures obtained before and during each matography with tandem mass spectrometry; LC/MS/MS) analy- PET scan (three ratings).
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